Parenteral dosage form of norepinephrine

ABSTRACT

The present invention relates to a ready-to-administer parenteral dosage form of norepinephrine which comprises an aqueous solution of norepinephrine, having an anti-oxidant which is not a sulfite anti-oxidant, wherein the dosage form is stable at room temperature for prolonged period of time.

This application is a continuation of U.S. application Ser. No.14/837,749, filed Aug. 27, 2015, which claims benefit to India PatentApplication No. 2759/MUM/2014, filed on Aug. 28, 2014, in the Governmentof India Patent Office, the disclosure of each of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a ready-to-administer parenteral dosageform of norepinephrine comprising an aqueous solution of norepinephrineand an anti-oxidant which is not a sulfite anti-oxidant, and wherein thedosage form is stable at room temperature.

BACKGROUND OF THE INVENTION

Norepinephrine is a sympathomimetic amine which functions as aperipheral vasoconstrictor (alpha-adrenergic action) and as an inotropicstimulator of the heart and dilator of coronary arteries(beta-adrenergic action). It is also known as l-arterenol, levarterenolor l-norepinephrine or noradrenaline.

Norepinephrine Bitartrate, a catecholamine is chemically(−)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt)monohydrate and has the following structural formula:

Norepinephrine (NE) is administered by intravenous infusion for bloodpressure control in certain acute hypotensive states (e.g.,pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia,myocardial infarction, septicemia, blood transfusion, and drugreactions) and as an adjunct in the treatment of cardiac arrest andprofound hypotension.

The commercial available injectable products of nor-epinephrinesolutions for example, nor-epinephrine pre-concentrate solution marketedin the United States under the brand name LEVOPHED® and the solution ofnor-epinephrine marketed by Cardinal Health Ltd., UK, use sodiumbisulfite or sodium metabisulfite as antioxidants. A clear warning withrespect to allergic reactions is included in the labels of theseproducts, which entails cautious use of these products by the patients.The use of sulphites or sulphur is reported to cause allergic-typereactions such as anaphylactic symptoms and life-threatening or lesssevere asthmatic episodes in certain susceptible persons. Indeed, thesymptoms of an allergic reaction to sulfites may exacerbate thecondition being treated. This exacerbation is especially critical giventhat nor-epinephrine is often used in emergency situations where furthercompromising a patient with an allergic reaction is disadvantageous.

Nor-epinephrine is known to be susceptible to oxidation and degradationin presence of oxygen, particularly when present in aqueous solutions.The degradation is undesirable as it results in loss of titer of theactive ingredient, formation of compounds which have undesirablephysiological effects, and the appearance of a dark colour, which makesthe solution offensive and unmarketable. Moreover, nor-epinephrine isknown to exist in two different stereoisomeric forms: R (−) isomer and S(+) isomer, the R(−) isomer is reported to have better affinity atvarious receptors and thus, more potent than the S(+) isomer. TheS-isomer has minimal to almost negligible activity.

The present inventors have discovered a parenteral dosage form whereinthe aqueous solution of nor-epinephrine is free of sulphite antioxidantand is ready to administer. The ready-to-administer aqueous solution inthe containers is not only stable at room temperature for prolongedperiods of time, but also shows minimal conversion to less activeS-isomer during the shelf life of the product. Further, the parenteraldosage form avoids the reconstitution or dilution step prior tointravenous infusion, thus eliminating the risk of any potentialcalculation or dilution error as well as risk of microbiologicalcontamination during handling.

SUMMARY OF THE INVENTION

The present invention provides a ready-to-administer parenteral dosageform comprising an aqueous solution comprising

-   -   a. therapeutically effective amount of norepinephrine or its        pharmaceutically acceptable salt    -   b. an anti-oxidant which is not a sulphite antioxidant,        wherein the solution is stable at room temperature.

DESCRIPTION OF THE INVENTION

The term norepinephrine, as used herein includes norepinephrine and/orits pharmaceutically acceptable salts such as norepinephrine bitartrateor norepinephrine hydrochloride or other salts. It is also known byother names such as l-arterenol, levarterenolol, l-norepinephrine ornoradrenaline.

The term “ready-to-administer” as used herein means that the drugsolution is sterile and suitable for direct intravenous infusion orinjection and no intermediate steps of dilution or reconstitution arerequired before parenteral administration of the drug solution to thepatient. The aqueous drug solution can be directly administeredparenterally from the container of the dosage form. The term“ready-to-administer” is synonymous with “ready-to-infuse” orready-to-inject” and is not to be read as the term “ready-to-use”aqueous solution. The term ‘ready-to-use’ in the art includes aqueouspreconcentrates which require a single step of dilution with an aqueousdiluent fluid such as water for injection or saline beforeadministration. The term “ready-to-administer” is also distinguishedfrom lyophilized products that require two steps, a first step ofreconstitution to form a preconcentrate and then a second step where thepreconcentrate is subjected to dilution with an aqueous infusion fluid.The ready-to-administer parenteral dosage form according to the presentinvention avoids the inconvenience of reconstituting or diluting aconcentrated parenteral formulation into infusion diluents prior toinfusion, as well as eliminates the risk of any potential calculation ordilution error as well as risk of microbiological contamination duringhandling. The volume of the aqueous drug solution according to thepresent invention is large i.e. when the end use container used in‘ready-to-administer’ parenteral dosage form is a prefilled syringe,then the volume of the aqueous solution may be about 50 ml to 100 ml.When the end use container is infusion bag, the volume of the aqueoussolution may be about 100 ml to 500 ml.

The term ‘sulfite anti-oxidant’ as used herein means any anti-oxidantcapable of providing sulfite, bisulfite, or metabisulfite anions inwater. For instance, sodium sulphite, sodium bisulfite, sodiummetabisulphite, sodium pyrosulphite and the like.

The term ‘stable at room temperature’ as used herein means that thedosage form is physically as well as chemically stable as demonstratedby compliance to acceptable specification when the dosage form is storedat room temperature (about 25° C.) for twelve months, preferablyeighteen months, more preferably 24 months or longer. Suitably, thesolution of nor-epinephrine remains physically stable, with noprecipitation or crystallization or color change upon storage and thevalue of percentage transmittance of the solution remaining greater than90%, preferably greater than 95% for the shelf life period of 18-24months when stored at room temperature. Suitably, the solution ofnor-epinephrine remains chemically stable when stored at roomtemperature (about 25° C.) and at refrigerated conditions (2-8° C.),wherein various parameters such as the drug content (assay ofnor-epinephrine) and content of related substances, i.e. known andunknown impurities remains within specified limits such as thosespecified according to ICH guidelines, upon storage for prolonged periodof time such as for at least 12 months, preferably for 18 months, morepreferably 24 months or longer. Suitably, the value of assay ofnor-epinephrine remains within the specified limit of 90-110% by weightof the label claim; the highest unknown impurity remains within thespecified limit of not more than 0.2%; the known Impurities B, C, D andE remains within the specified limit of not more than 0.29% and theImpurity A remains within the specified limit of not more than 1.0%. Thetotal impurities remain below 2.0%, preferably below 1.0%.

The ready-to-administer parenteral dosage form of the present inventioncomprises an aqueous solution comprising therapeutically effectiveamount of norepinephrine or its pharmaceutically acceptable salt and ananti-oxidant which is not a sulfite anti-oxidant. Suitably, in onepreferred embodiment, the pharmaceutically acceptable salt ofnor-epinephrine is nor-epinephrine bitartrate. Suitably, nor-epinephrineor its pharmaceutically acceptable salt may be present in theready-to-administer parenteral dosage form in an amount ranging fromabout 0.001 mg/ml to 0.4 mg/ml, preferably from about 0.002 mg/ml to 0.2mg/ml. In one embodiment, norepinephrine is present in the aqueoussolution in an amount ranging from about 0.001 mg/ml to about 0.2 mg/ml.In one embodiment, nor-epinephrine or its pharmaceutically acceptablesalt is nor-epinephrine bitartrate and it is present in the aqueoussolution in an amount ranging from about 0.002 mg/ml to about 0.4 mg/ml.

Suitably, the ready-to-administer parenteral dosage form of the presentinvention comprises an anti-oxidant which is not a sulphiteanti-oxidant. Such anti-oxidants, may be selected form, but not limitedto butylated hydroxyl anisol, ascorbic acid, propyl gallate, vitamin E,alpha-tocopherol, butylated hydroxyl toluene and the like. Theparenteral dosage form of the present invention is devoid of sulphurcontaining and/or sulfite anti-oxidants such as sodium sulfite, sodiumbisulfite, sodium metabisulfite or mixtures thereof. In a preferredembodiment, the anti-oxidant is butylated hydroxyanisole. Suitably,butylated hydroxyanisole is present in an amount ranging from about0.001 mg/ml to about 0.01 mg/ml, preferably from about 0.001 mg/ml toabout 0.005 mg/ml.

Suitably, the aqueous solution of the present invention may furthercomprise other parentally acceptable excipients, including but notlimited to, osmotic/tonicity adjusting agents, chelating agents, pHadjusting agents, buffers.

Suitably, the aqueous solution according to the present invention have apH in the range of about 3.0 to about 4.5, preferably from about 3.5 toabout 4.2. The parenteral dosage form shows best stability at this pHrange. The pH of the solution may be adjusted in the desired range byuse of a pH adjusting agents and or a buffering agent known in thepharmaceutical art or it may be auto-adjusted in the desired range bythe ingredients present in the solution of the present invention. The pHadjusting and/or buffering agent that may be used include, but are notlimited to sodium hydroxide, hydrochloric acid, sulfuric acid, citricacid, acetic acid, tartaric acid, tromethamine, potassium hydroxide andthe like and mixtures thereof. The aqueous solution in the parenteraldosage form of the present invention has an osmolality in the range ofabout 250-375 mOsm/kg, preferably 270-330 mOsm/kg. The osmolality of theaqueous solution in the dosage form of the present invention is adjustedby addition of an osmotic agent or tonicity adjusting agent. Thetonicity adjusting agent that may be used according to the presentinvention may be selected from, but are not limited to, sodium chloride,potassium chloride, calcium chloride, mannitol, glycerol, sorbitol,propylene glycol, dextrose, sucrose, and the like and mixtures thereof.According to one preferred embodiment, the osmotic agent is sodiumchloride and it may be used in an amount ranging from about 0.3% w/v toabout 1.0% w/v. The aqueous solution of nor-epinephrine may furthercomprise a chelating agent. The chelating agent that may be used isselected form, but is not limited to, disodium edetate dihydrate,disodium edetate, edetic acid, ethylenediamine tertaacetic acid,diethylenetriamine pentaacetic acid. A preferred chelating agent isethylenediamine tertaacetic acid or disodium edetate dehydrate.

In a preferred embodiment, the aqueous solution of nor-epinephrineaccording to the present invention has a dissolved oxygen level of lessthan 4 ppm, preferably less than 2 ppm, more preferably less than 1 ppm.This is achieved by purging the aqueous solution with an inert gas suchas nitrogen or argon or helium.

The ready-to-administer parenteral dosage form of the present inventioncomprises a suitable container which contains the aqueous solution ofnorepinephrine. The container may be optionally further packaged in asecondary packaging. In one embodiment, either of the container or thesecondary packaging is designed to protect the solution ofnor-epinephrine from light. The secondary packaging may comprise asuitable pouch, such as an aluminium pouch and/or a carton packaging,which may further contain an oxygen scavenger. Preferably, the containeris designed for ready-to-infuse or ready-to-inject the aqueous solutionof norepinephrine to the patient. The container is made up of a suitablematerial such as plastic or any other polymeric material. The containermay include one or more layers of such materials. Suitably, suchmaterials may include but are not limited to, polyolefin polymers,polyethylene, polypropylene; cyclo olefin polymers, cyclo olefincopolymers, polypropylene based polyolefin polymers; polycarbonates;modified polyolefin-polyethylene polymers or styrene-polyolefin basedpolymers and block co-polymers thereof. Suitably, the container does nothave material that contains borate or boron. Preferably, according toone embodiment, the container has non-glass components. Suitably, thematerial of construction is such that these containers are transparentwhich makes it possible to carry out visual inspection of the drugsolution prior to and during administration of the drug solution. Anychange in colour or any particulate matter can be detected easily byvisual inspection, which ensures safety.

In a preferred particular embodiment of the present invention, thecontainer is a pre-filled syringe. The pre-filled syringe is made up ofa material having at least one non-glass component. The barrel of thepre-filled syringe is preferably made up of appropriate plastic orpolymeric material. In a preferred aspect, the syringe comprises abarrel made up of cyclic olefin polymer, cyclic olefin copolymer,polypropylene, polycarbonate and the like. The syringe may furthercomprise an elastomeric tip cap, made up of material such aschloro-butyl formulation. The syringe may comprise a plunger stoppermade up of rubber material such as bromo-butyl rubber. The syringe maybe further packed in a secondary packaging to protect from light. Thesecondary packaging comprises a suitable pouch, such as an aluminiumpouch and a carton packaging. The pouch may further contain an oxygenscavenger. In this embodiment, norepinephrine or its pharmaceuticallyacceptable salt may be present in the aqueous solution in an amountranging from about 0.025 mg/ml to about 0.4 mg/ml, preferably from about0.05 mg/ml to about 0.2 mg/ml. In one particularly preferred embodiment,norepinephrine or its pharmaceutically acceptable salt isnor-epinephrine bitartrate and it is present in the aqueous solution inan amount of 0.2 mg/ml which is approximately equivalent to 0.1 mg/ml ofnorepinephrine base. In this embodiment, the volume of the aqueoussolution in pre-filled syringe may vary from about 50 ml to about 100ml. According to preferred embodiment, the ready-to-administerparenteral dosage form provides large volume pre-filled syringes, whichcan accommodate a volume of at least 50 ml, preferably about 50 ml to100 ml.

In another preferred embodiment of the present invention, the containeris an infusion bag. In this embodiment, norepinephrine or itspharmaceutically acceptable salt is present in the aqueous solution inan amount ranging from about 0.001 mg/ml to about 0.2 mg/ml, preferablyfrom about 0.004 mg/ml to about 0.15 mg/ml, more preferably from about0.01 mg/ml to about 0.1 mg/ml. In one preferred embodiment,norepinephrine is present in the aqueous solution in an amount of 0.016mg/ml. In one preferred embodiment, norepinephrine is present in theaqueous solution in an amount of 0.032 mg/ml. The volume of aqueoussolution in each bag may vary from about 100 ml to about 500 ml.According to preferred embodiments of the present invention, theready-to-administer parenteral dosage form provides large volumeinfusion bags, which can accommodate a volume of at least 100 ml,preferably from about 100 ml to 500 ml. The aqueous solution comprisesthe nor-epinephrine at a concentration which allows direct infusion ofthe aqueous solution in the desired dose to the patient without the needof further dilution. The containers have volume and dimensions such thatit allows use of drug solutions that can be directly infused to thepatients without any step of reconstitution or dilution. Preferably, theconcentration and volume is such that for patient with an average bodysurface area, only one unit of the dosage form is sufficient to deliverthe prescribed dose of the drug. The containers are also easy to handleand transport.

According to another preferred particular embodiment of the presentinvention, the aqueous solution of norepinephrine is ready-to-infuse andcontainer is designed for ready-to-infuse administration. In onepreferred embodiment, the container is a flexible infusion containersuch an infusion bag or a flexible pouch or a soft bag. Particularly,the flexible infusion container is not impermeable in nature andpossesses some permeation characteristics and the aqueous solution ofnor-epinephrine remains in contact with these materials of the containerthroughout the shelf life of the dosage form. The container may besingle or multiple layered and made up of a suitable material such asplastic or any other polymeric material. Such materials may be selectedfrom, but not limited to, polyolefin polymers-polyethylene,polypropylene; cyclo olefin polymers, cyclo olefin copolymers,polypropylene based polyolefin polymers; modifiedpolyolefin-polyethylene polymers or styrene-polyolefin based polymersand block co-polymers thereof. These plastic materials of the containermay further have one or more outer layers which may be made up ofpolyamide, modified polyolefin, polypropylene, styrene-polyolefin basedpolymers and block co-polymers thereof and the like. In one specificembodiment, the flexible infusion containers are made up of an outerlayer of polyamide 11, a middle tie of modified polyolefin and an innerlayer of linear low density polyethylene. This type of containers have awater vapour transmission rate of 2 g (m²·day) when measured at (40°C./90% relative humidity); oxygen transmission rate of 900 ml/(m²·24hour·atm) when measured at (23° C./0% relative humidity) and carbondioxide transmission rate of 600 ml/(m²·24 hour·atm) when measured at23° C./0% relative humidity. Such containers are available commerciallyand are manufactured by Hosokawa as Polyelite AE-1.

In one preferred embodiment the flexible infusion containers may be madeup of a material comprising a polymer of cyclic olefin such ascycloolefin homopolymer or cycloolefin copolymer or mixture thereof.Specifically, in a particular embodiment, the container comprises aninner layer made up of a cycloolefin polymer, a middle layer made up oflinear low density polyethylene polymer and an outer layer made up oflow density polyethylene polymer. Such containers are availablecommercially and are manufactured by Hosokawa as Polyelite EHC film bag.In another embodiment, the flexible infusion containers may be made upof an outer layer of polypropylene polymer withstyrene-ethylene-butylene (SEB) block copolymer and a middle and innerlayer made up of polypropylene based polyolefin polymer withstyrene-ethylene butylene block copolymer. Such containers are availablecommercially and are manufactured by Technoflex These type of containershave a water vapour transmission rate of 0.62 g (m²·day) when measuredat 23° C./60% relative humidity; oxygen permeability of 1110 ml/(m²·24hour·atm) when measured at 23° C./40% relative humidity and carbondioxide transmission rate of 5149 ml/(m²·24 hour·atm). Alternatively,the flexible container used is made up of multilayer polyolefin film(M312 and M312A) with a multilayered polyolefin tubing (M916 and M916A).Such containers are available under the brand names of Sippex.

In one embodiment, the flexible infusion containers may include aMinitulipe® infusion port which is an infusion connector having threeassembled parts including a central stopper made up of chlorobutylrubber (latex free); an upper breakable part and a bottom part, bothmade up of polycarbonate. In one embodiment, the flexible infusioncontainer contains a delivery port end for insertion of an infusion setcannula/needle. In one embodiment, the flexible infusion container/bagand the delivery port connecting to the infusion needle form a systemwhereby during administration of the solution to the patient the vacuumcreated by outgress of solution is accommodated by the elasticity orflexibility of the infusion bag instead of ingress of externalnon-sterile air. The dosage form can advantageously maintain thesterility of the solution until it reaches the patient.

In one embodiment, the flexible infusion container includes a thermallyresealable portion that is fusible in response to thermal energy, and acontainer body having a sealed empty chamber in fluid communication withthe resealable portion for receiving therein the aqueous solution of thepresent invention. The method of filling the container includespenetrating the resealable portion with an injection member andintroducing the aqueous solution of the present invention into thechamber, withdrawing the injection member while engaging the base of thebody to substantially prevent axial movement of the body, and applyingthermal energy to the resealable portion to thermally fuse thepenetrated region thereof. Such systems are elaborated in Unites Statespatent number U.S. Pat. No. 7,992,597, which is incorporated herein byreference.

In another embodiment, the flexible infusion container may include achamber for receiving aqueous solution of the present invention and athermoplastic portion in fluid communication with the chamber. Thethermoplastic portion defines a penetrable region that is penetrable bya filling member and is heat resealable to hermetically seal an aperturetherein by applying laser radiation at a predetermined wavelength andpower and in a predetermined time period. Such systems are elaborated inUnites States patent number U.S. Pat. No. 7,490,639, which isincorporated herein by reference.

In yet another embodiment, the flexible infusion container include asealed chamber; a first penetrable septum in fluid communication withthe chamber that is formed of an elastic material and is penetrable by afirst injection member to fill the first chamber with the aqueoussolution of the present invention therethrough; and a second penetrableseptum movable between first and second positions. In the firstposition, at least a portion of the second septum is spaced away fromthe first septum to allow the injection member to penetrate the firstseptum and aseptically or sterile fill the chamber with the aqueoussolution of the present invention therethrough. In the second position,the portion of the second septum overlies and seals a resultinginjection aperture in the first septum after withdrawal of the firstinjection member therefrom, and is penetrable by a second injectionmember to penetrate the first and second septums and withdraw the filledaqueous solution of the present invention from the chamber and throughthe second injection member. Such systems are elaborated in UnitesStates patent application number US20130333796, which is incorporatedherein by reference.

In one embodiment, the ready-to-administer dosage form of the presentinvention further comprises secondary packaging that surrounds theflexible infusion container. In one embodiment, the secondary packagingis designed to protect the solution from light. The secondary packagingmay comprise a second container such as a pouch or overwrap or carton.In preferred embodiments, the secondary packaging pouch or overwrap orcarton is made up of a suitable light protective material such asaluminum. It may further comprise an oxygen scavenger. In one preferredembodiment, the space between the flexible infusion container andsecondary packaging is occupied with an inert gas. The inert gas may beused to flush out or replace the air from the space between the flexibleinfusion container and the light protective secondary packaging. Theinert gas that may be used include, but is not limited to nitrogen,argon and helium. In one specific embodiment, secondary packagingcomprises an aluminium pouch containing an oxygen scavenger. In anotherembodiment, the space between the flexible infusion container andsecondary packaging is occupied with an inert gas such as nitrogen.

In one specific embodiment, there is provided a ready-to-administerparenteral dosage form comprising an aqueous solution comprisingtherapeutically effective amount of norepinephrine or itspharmaceutically acceptable salt, an antioxidant which is not a sulphiteantioxidant selected from butylated hydroxyl anisol, ascorbic acid,propyl gallate, vitamin E or alpha-tocopherol, optionally a chelatingagent, a tonicity adjusting agent and a pH adjusting agent to adjust thepH of solution in the range of 3.0 to 4.5 and wherein the aqueoussolution is stable at room temperature.

In another specific embodiment, there is provided a ready-to-administerparenteral dosage form comprising an aqueous solution comprisingtherapeutically effective amount of norepinephrine or itspharmaceutically acceptable salt, butylated hydroxyl anisol as anantioxidant, optionally a chelating agent, a tonicity adjusting agentand a pH adjusting agent to adjust the pH of solution in the range of3.0 to 4.5 and wherein the aqueous solution is stable at roomtemperature.

In one specific embodiment, there is provided a ready-to-administerparenteral dosage form comprising an aqueous solution comprisingtherapeutically effective amount of norepinephrine or itspharmaceutically acceptable salt in an amount ranging from about 0.001mg/ml to about 0.4 mg/ml, an antioxidant which is not a sulphiteantioxidant, optionally a chelating agent, a tonicity adjusting agentand a pH adjusting agent to adjust the pH of solution in a range of 3.0to 4.5, wherein the aqueous solution is filled in a container, whichcontainer is optionally further packaged in a secondary packaging,wherein either the container or the secondary packaging is designed toprotect the solution from light and wherein the aqueous solution isstable at room temperature.

In one specific embodiment, there is provided a ready-to-administerparenteral dosage form comprising an aqueous solution comprisingtherapeutically effective amount of norepinephrine or itspharmaceutically acceptable salt in an amount ranging from about 0.001mg/ml to about 0.4 mg/ml, an antioxidant which is not a sulphiteantioxidant, optionally a chelating agent, a tonicity adjusting agentand a pH adjusting agent to adjust the pH of solution in a range of 3.0to 4.5, wherein the aqueous solution is filled in a container, whichcontainer is optionally further packaged in a secondary packaging,wherein either the container or the secondary packaging is designed toprotect the solution from light, further wherein the container is madeup of a material selected from the group comprising polyolefin polymers,polyethylene, polypropylene; cyclo olefin polymers, cyclo olefincopolymers; polypropylene based polyolefin polymers; polycarbonates;modified polyolefin-polyethylene polymers; styrene-polyolefin basedpolymers and block co-polymers thereof and wherein the aqueous solutionis stable at room temperature. In one preferred embodiment, there isprovided a ready-to-administer parenteral dosage form comprising anaqueous solution comprising therapeutically effective amount ofnorepinephrine bitartrate in an amount ranging from about 0.002 mg/ml toabout 0.4 mg/ml, butylated hydroxyanisole as an antioxidant, a chelatingagent, a tonicity adjusting agent and a pH adjusting agent to adjust thepH of solution in a range of 3.0 to 4.5, wherein the aqueous solution isfilled in a container, which container is optionally further packaged ina secondary packaging, wherein either the container or the secondarypackaging is designed to protect the solution from light and wherein theaqueous solution is stable at room temperature.

In another preferred embodiment, there is provided a ready-to-administerparenteral dosage form comprising an aqueous solution comprisingtherapeutically effective amount of norepinephrine bitartrate in anamount ranging from about 0.002 mg/ml to about 0.4 mg/ml, butylatedhydroxyanisole as an antioxidant, a chelating agent, a tonicityadjusting agent and a pH adjusting agent to adjust the pH of solution ina range of 3.0 to 4.5, wherein the aqueous solution is filled in acontainer, which container is optionally further packaged in a secondarypackaging, wherein either the container or the secondary packaging isdesigned to protect the solution from light, further wherein thecontainer is made up of a material selected from the group comprisingpolyolefin polymers, polyethylene, polypropylene; cyclo olefin polymers,cyclo olefin copolymers; polypropylene based polyolefin polymers;polycarbonates; modified polyolefin-polyethylene polymers;styrene-polyolefin based polymers and block co-polymers thereof, andwherein the aqueous solution is stable at room temperature.

In one particularly preferred embodiment, there is provided aready-to-administer parenteral dosage form comprising an aqueoussolution comprising therapeutically effective amount of norepinephrinebitartrate in an amount ranging from about 0.002 mg/ml to about 0.4mg/ml, butylated hydroxyanisole as an antioxidant, a chelating agentselected from disodium edetate, disodium edetate dihydrate, edetic acid,ethylenediamine tertaacetic acid or diethylenetriamine pentaacetic acid,a tonicity adjusting agent selected from sodium chloride, potassiumchloride, calcium chloride, mannitol, glycerol, sorbitol, propyleneglycol, dextrose, sucrose and a pH adjusting agent to adjust the pH ofsolution in a range of 3.0 to 4.5, wherein the aqueous solution isfilled in a container, which container is optionally further packaged ina secondary packaging, wherein either the container or the secondarypackaging is designed to protect the solution from light and wherein theaqueous solution is stable at room temperature.

In one particularly preferred embodiment, there is provided aready-to-administer parenteral dosage form comprising an aqueoussolution comprising therapeutically effective amount of norepinephrinebitartrate in an amount ranging from about 0.002 mg/ml to about 0.4mg/ml, butylated hydroxyanisole as an antioxidant, a chelating agentselected from disodium edetate, disodium edetate dihydrate, edetic acid,ethylenediamine tertaacetic acid or diethylenetriamine pentaacetic acid,a tonicity adjusting agent selected from sodium chloride, potassiumchloride, calcium chloride, mannitol, glycerol, sorbitol, propyleneglycol, dextrose, sucrose and a pH adjusting agent to adjust the pH ofsolution in a range of 3.0 to 4.5, wherein the aqueous solution isfilled in a container, which container is optionally further packaged ina secondary packaging, wherein either the container or the secondarypackaging is designed to protect the solution from light further whereinthe container is made up of a material selected from the groupcomprising polyolefin polymers, polyethylene, polypropylene; cycloolefin polymers, cyclo olefin copolymers; polypropylene based polyolefinpolymers; polycarbonates; modified polyolefin-polyethylene polymers;styrene-polyolefin based polymers and block co-polymers thereof, andwherein the aqueous solution is stable at room temperature.

In one particularly preferred embodiment, there is provided aready-to-administer parenteral dosage form comprising an aqueoussolution comprising therapeutically effective amount of norepinephrinebitartrate in an amount ranging from about 0.01 mg/ml to about 0.2mg/ml, butylated hydroxyanisole as an antioxidant, a chelating agentselected from disodium edetate dihydrate, disodium edetate, edetic acid,ethylenediamine tertaacetic acid or diethylenetriamine pentaacetic acid,a tonicity adjusting agent selected from sodium chloride, potassiumchloride, calcium chloride, mannitol, glycerol, sorbitol, propyleneglycol, dextrose, sucrose and a pH adjusting agent to adjust the pH ofsolution in a range of 3.0 to 4.5, wherein the aqueous solution isfilled in a container, which container is optionally further packaged ina secondary packaging, wherein either the container or the secondarypackaging is designed to protect the solution from light further whereinthe container is made up of a material selected from the groupcomprising polyolefin polymers, polyethylene, polypropylene; cycloolefin polymers, cyclo olefin copolymers; polypropylene based polyolefinpolymers; polycarbonates; modified polyolefin-polyethylene polymers;styrene-polyolefin based polymers and block co-polymers thereof, furtherwherein the secondary packaging comprises a light resistant pouch suchas an aluminium pouch and an oxygen scavanger and wherein the aqueoussolution is stable at room temperature.

The present inventors have surprisingly found that theready-to-administer parenteral dosage form of the present invention isstable at room temperature for prolonged period of time inspite ofhaving large volume aqueous solution in large volume infusioncontainers. The aqueous solution of norepinephrine is stable at roomtemperature for extended periods of time in the liquid state, withouthaving to undergo a step of freeze-drying or reconstitution or dilution.That is it represents a substantial advancement over the art, and amajor convenience to potential patients.

The ready-to-administer parenteral dosage form of the present inventionis physically and chemically stable at room temperature (about 20-25°C.) as well as at lower temperatures such as 2-8° C. for prolongedperiod of time, and meets all acceptable stability criteria's uponstorage for prolonged periods such as for at least 18 months, preferably2 year or more. The solution remains physically stable, with noprecipitation or crystallization or color change upon storage. Thepercentage transmittance values, which are indicators of clarity andphysical stability of a solution, surprisingly remains greater than 90%,preferably greater than 95%, more preferably greater than 97% for theshelf life period of 18-24 months.

The ready-to-administer parenteral dosage form of the present inventioncomprising the aqueous solution of nor-epinephrine also remainschemically stable when subjected to long term stability testing at roomtemperature (25° C./60% relative humidity) and at refrigeratedconditions (2-8° C.). Various parameters such as the drug content (assayof nor-epinephrine) and content of related substances, i.e. known andunknown impurities remains within specified limits such as thosespecified according to ICH guidelines, upon storage for prolonged periodof time such as for at least 12 months, preferably for 18 months, morepreferably 2 year or more. Suitably, the value of assay ofnor-epinephrine remains within the specified limit of 90-110% of thelabel claim. Further, the total impurities remains below 2.0%,preferably less than 1.0% more preferably less than 0.5% by weight andhighest unknown impurity remains below 0.2%. Furthermore, the knownrelated substances, i.e. Impurities B, C, D and E remains within thespecified limit of not more than 0.29% and Impurity A remains within thespecified limit of not more than 1.0%.

In one preferred embodiment, the present invention thus provides aready-to-administer parenteral dosage form comprising an aqueoussolution comprising therapeutically effective amount of norepinephrineor its pharmaceutically acceptable salt, an anti-oxidant which is not asulphite antioxidant, wherein the parenteral dosage form is stable atroom temperature and wherein the value of total impurities in theaqueous solution is not more than 2.0% by weight upon storage at roomtemperature or lower for at least 12 months.

Surprisingly, the inventors of the present invention found that theready-to-administer parenteral dosage form of the present inventionprovided a very minimal conversion of the nor-epinephrine R-isomer,which is the active form, into the S-isomer. This is particularly ofgreat significance because S-isomer has almost negligible activity. TheS-isomer levels remains very low, preferably less than 5%, morepreferably less than 4% upon storage at room temperature or lowertemperatures for at least 12 months or 18 months or more. The conversionof R-isomer to S-isomer was significantly lower compared to the marketedproduct Levophed® upon storage under similar conditions. Upon storage ofInnovator's US marketed product “Levophed® under similar conditions andanalysing at the end of shelf life (18 months), the S-isomer level wasabout 6.7%. Upon storage of Innovator's European marketed product“Levophed® under similar conditions, the S-isomer level was about 15.9%after storage for 18 months. In contrast, the present invention providesa ready-to-administer parenteral dosage form comprising an aqueoussolution comprising therapeutically effective amount of norepinephrineor its pharmaceutically acceptable salt and an anti-oxidant which is nota sulphite antioxidant and wherein the solution when stored at roomtemperature or lower for 12 months has less than 4% of S-isomer content,preferably less than 4% of S-isomer content. According to one preferredembodiment of the present invention wherein the dosage form is apre-filled syringe, and wherein the aqueous solution has a pH in therange of about 3.0 to 4.5, the S-isomer content was about 1.7% uponstorage at room temperature or lower for 12 months. According to anotherpreferred embodiment of the present invention wherein the dosage form isin a flexible infusion bag, the S-isomer level was about 4.5% uponstorage at room temperature or lower for 18 months. In one preferredembodiment, the present invention thus provides a ready-to-administerparenteral dosage form comprising an aqueous solution comprisingtherapeutically effective amount of norepinephrine or itspharmaceutically acceptable salt, an anti-oxidant which is not asulphite antioxidant, wherein the solution when stored at roomtemperature for twelve months has less than 4% of S-isomer content.

The ready-to-administer parenteral dosage form of norepinephrine of thepresent invention, show improved stability, in particular stabilityagainst auto-oxidation and thermal stability, and consequently enhancedstorage shelf-life of at least 18 months, preferably 2 year or more,even when stored at room temperature. A prior known solution ofnor-epinephrine marketed by Cardinal Health Ltd., UK, which isstabilized by sodium metabisulphite, is stable when stored at 2-8° C.for six months. The shelf life of the product is only six months whenstored at 2-8° C. Present inventors prepared similar dosage form andstability testing at room temperature confirmed that norepinephrine wasunstable in the prior known sodium metabisulphite containing dosage formwhen stored at room temperature. While the shelf life of marketedCardinal's product is 6 months, when stored at 2-8° C., the parenteraldosage form according to one embodiment of the present invention wassurprisingly found to be stable even at room temperature (25° C./60% RH)(besides being stable at 2-8° C.) for prolonged period of time of atleast 12 months, preferably 18 months, more preferably 2 year or more.The ready-to-administer parenteral dosage form of the present inventionnot only have better stability profile compared to marketed Cardinal'sproduct, but also compared to marketed Levophed® product, which is aconcentrated product having 1 mg/ml nor-epinephrine. As per Levophed®product label, the product upon dilution is stable only upto 24 hours atroom temperature.

Suitably, the ready-to-administer dosage form of the present inventionis sterile. The term “sterile” or ‘sterilized’ as used in the context ofthe invention, means that the solution has been brought to a state ofsterility and has not been subsequently exposed to microbiologicalcontamination, i.e. the sterility of the solution present in thecontainer has not been compromised. The solution complies with thesterility requirements of the standard Pharmacopoeias like United StatesPharmacopoeias (USP). Sterilization may be achieved by suitabletechniques such as filtration sterilization, radiation sterilization andthe like. In one preferred embodiment, the parenteral dosage form of thepresent invention is subjected to sterilization by membrane filtrationof the aqueous solution.

The ready-to-administer parenteral dosage form of the present inventioncan be prepared by a process involving following exemplary steps—Purgingwater for injection with Nitrogen gas to bring dissolved oxygen levelbelow 2 PPM, preferably below 1 PPM. Preferably, the purging should becarried out during the whole process to maintain dissolved oxygen levelof less than 1 PPM. Dissolving the chelating agent such as disodiumedetate dihydrate in water for injection followed by addition anddissolution of anti-oxidant such as butylated hydroxyanisole.Dissolution may be carried out by warming the solution to an elevatedtemperature, if required along with stirring. Cooling the solution toroom temperature. Adding and dissolving an osmotic agent such as forexample, sodium chloride to the above solution. Adding the drug,norepinephrine bitartarate, to the above solution and obtaining finalsolution by making up the volume to desired level using water forinjection. Checking and if required adjusting the pH of the solution inthe range of pH 3.0 to 4.5 using a pH adjusting agent and/or bufferingagent such as by using buffers or use of an acid/base. Asepticallyfiltering the solution using a membrane filter, followed by asepticallyfilling the solution into a container such as for example a syringe oran infusion bag, followed by stoppering or sealing of the container.Optionally, packaging this primary container further with a secondarypackaging. This may be achieved by overwrapping the primary container bya light protective secondary packaging such as an aluminum pouch andsealing the pouch. An oxygen scavenger may be placed in the spacebetween the primary container and the light protective secondarypackaging. Further, the space between the infusion bag and the aluminumpouch may be replaced with an inert gas such as nitrogen gas.

Hereinafter, the invention will be more specifically described by way ofExamples. The examples are not intended to limit the scope of theinvention and are merely used as illustrations.

Example 1

TABLE 1 Ready-to-administer parenteral dosage form compositionIngredients Amount in milligrams Norepinephrine bitartarate equivalent 5to norepinephrine base . . . Butylated hydroxyanisole 0.15 Disodiumedetate dihydrate 5 Sodium chloride 450 Sodium hydroxide/hydrochlorideacid q.s. to pH 3.0 to 4.5 Water for injection q.s. to 50 ml

The water for injection was purged with nitrogen until dissolved oxygenlevel below 1.0 ppm is achieved. Aqueous solution of disodium edetate,sodium chloride was prepared separately. Butylated hydroxyanisole wasdissolved in warm water. Subsequently, norepinephrine bitartarate wasthen added and pH was adjusted in the range of 3.0 to 4.5 usingacid/base and volume was made. The oxygen level was monitored to bebelow 1.0 ppm by nitrogen purging. The solution so obtained was filteredaseptically through a 0.2 micron membrane filter and aseptically filledinto non glass container which is a cyclo olefin copolymers syringe withfill volume of 50 ml. The filled syringe was aseptically stoppered witha bromo-butyl plunger. The filled syringes were overwrapped in aluminumpouch, for light protection. The space between the filled syringe andthe aluminum pouch was replaced with nitrogen gas. An oxygen scavengerwas placed in the space between the syringe and the aluminum pouch.

The observed values for various parameters after storage for 18 month atcontrolled room temperature of 25±2° C. and 60%±5% relative humidity,are given below in Table 2:

TABLE 2 Observations of various parameters Parameters Initial 12 monthAssay of nor-epinephrine 105.11 105.4 S-isomer 0.18 4.49 Impurity A NDND Impurity B 0.005 0.024 Impurity C ND ND Impurity D 0.06 0.06 ImpurityE ND ND Highest unknown Impurity 0.06 0.11 Total Impurities 0.12 0.39 pH3.7 3.73 % Transmittance 99.96 99.8 at 650 nm ND—Not detected

It was found that upon storage for 18 months at room temperature, thesolutions remained clear and colourless, without any signs ofprecipitation or crystallization or colour change upon storage. This isevident by the percentage transmittance values which were more than 95%at all time points until 18 months. The observed percentagetransmittance value after storage for 18 months was found to be morethan 95%. It was further observed that the value of assay ofnor-epinephrine was well within the specified limit of 90-110% of thelabel claim. Further, the solution had less than 0.5% of totalimpurities and less than 0.2% of highest unknown impurity upon storageat room temperature for 18 months. The S-isomer content was less than5%. The Impurities A-E were either not detected or were present innegligible amounts, well within the specified limits.

Example 2

TABLE 3 Aqueous solution of Norepinephrine in infusion bag IngredientsAmount in milligrams per ml Norepinephrine bitartarate equivalent to0.016 norepinephrine base . . . Butylated Hydroxyanisole 0.003 DisodiumEdetate Dihydrate 0.1 Sodium chloride 8.5 Sodium hydroxide/hydrochlorideacid q.s. to pH 3.0 to 4.5 Water for Injection q.s. to 1 mL

The water for injection was purged with nitrogen until dissolved oxygenlevel below 1.0 ppm is achieved. Aqueous solution of disodium edetate,sodium chloride was prepared separately. Butylated hydroxyanisole wasdissolved in warm water. Subsequently, norepinephrine bitartarate wasthen added and pH was adjusted in the range of 3.0 to 4.5 usingacid/base and volume was made. The oxygen level was monitored to bebelow 1.0 ppm by nitrogen purging. The solution so obtained was filteredaseptically through a 0.2 micron membrane filter and aseptically filledinto a suitable infusion container made up of polyethylene polymer involumes of 100 ml each. The filled infusion bags were overwrapped inaluminum pouch, for light protection. The space between the infusion bagand the aluminum pouch was replaced with nitrogen gas. An oxygenscavenger was placed in the space between the infusion bag and thealuminum pouch.

The ready-to-administer dosage form of nor-epinephrine was subjected toaccelerated stability conditions, such as at controlled roomtemperature, i.e. 25° C./40% relative humidity and at 2-8° C. The drugcontent and related substances, i.e. known and unknown impurities wereanalyzed. The details are given below in Table 4:

TABLE 4 Results of the stability testing Stored at 25 ± 2° C. and 60% ±5% relative humidity for 12 Parameters Initial month Assay 101 100S-isomer 0.31 1.7 Impurity A ND ND Highest unknown Impurity 0.04 0.14Total impurities 0.1 0.27 pH 4.2 4.2 % Transmittance 99.9 99.8 at 650 nmND—Not detected

It was observed that the value of assay of nor-epinephrine was wellwithin the specified limit of 90-110% of the label claim. Further, thesolution showed a very small increase in the impurities such as knownand unknown. The highest unknown impurity was very low i.e 0.2%. Theaqueous solution did not show any signs of precipitation orcrystallization or discoloration. The s-isomer content, which is aninactive isomer, was unexpectedly found to be very low, much lower than2%.

The invention claimed is:
 1. An aqueous solution comprising norepinephrine or its pharmaceutical acceptable salt, an antioxidant comprising butylated hydroxyl anisole in an amount ranging from about 0.001 mg/ml to about 0.01 mg/ml, wherein said aqueous solution is stable at room temperature for at least 12 months.
 2. The aqueous solution according to claim 1, wherein said aqueous solution is in a container and is a ready-to-infuse solution.
 3. The aqueous solution according to claim 1, wherein the norepinephrine or its pharmaceutically acceptable salt is norepinephrine bitartrate.
 4. The aqueous solution according to claim 3, wherein the norepinephrine bitartrate is present in an amount ranging from about 0.001 mg/ml to about 0.4 mg/ml.
 5. The aqueous solution according to claim 1, wherein said solution further comprises an antioxidant, which is not a sulphite antioxidant, selected from the group consisting of butylated hydroxyl toluene, ascorbic acid, propyl gallate, vitamin E and alpha-tocopherol.
 6. The aqueous solution according to claim 1, wherein the pH of the aqueous solution is in the range of about 3.0 to about 4.5.
 7. The aqueous solution according to claim 2, wherein the aqueous solution in the container is further packaged in a secondary packing, wherein either the container or secondary packing is designed to protect the solution of nor- epinephrine from light.
 8. The aqueous solution according to claim 7, wherein the container comprises material selected from the group consisting of polyolefin polymers, polyethylene, polypropylene, cyclo-olefin polymers, cyclo-olefin copolymers, polypropylene based polyolefin polymers, polycarbonates, modified polyolefin-polyethylene polymers, and styrene-polyolefin based polymers and block co-polymers thereof.
 9. The aqueous solution according to claim 7, wherein the secondary packing comprises an aluminum pouch and an oxygen scavenger.
 10. The aqueous solution according to claim 1, wherein the aqueous solution when stored at room temperature for 12 months has less than 4% of S-isomer content.
 11. The aqueous solution according to claim 1, wherein the aqueous solution has total impurities not more than 2.0% by weight after storage at room temperature for at least 12 months.
 12. A stable parenteral dosage form comprising a ready-to-infuse aqueous solution of from about 0.001 mg/ml to about 0.4 mg/ml norepinephrine, or its pharmaceutical acceptable salt, and butylated hydroxyl anisole in an amount up to about 0.01 mg/ml, said aqueous solution having an osmolality in the range of about 250-375 mOsm/kg, and wherein the solution is stable at room temperature for at least 12 months.
 13. A stable parenteral dosage form comprising an aqueous solution of from about 0.001 mg/ml to about 0.4 mg/ml norepinephrine, or its pharmaceutical acceptable salt, and butylated hydroxyl anisole in an amount up to about 0.01 mg/ml, wherein said solution has more than 95% transmittance values and less than 0.5% of highest unknown impurity upon storage at room temperature for at least 12 months.
 14. A ready-to-administer parenteral dosage form comprising a solution of from about 0.001 mg/ml to about 0.4 mg/ml norepinephrine bitartrate, butylated hydroxyl anisole in an amount up to about 0.01 mg/ml, a chelating agent, and an osmogen in an infusion container, wherein the pH of the aqueous solution is 3.0 to 4.5 and a dissolved oxygen level below 2 ppm, and wherein the solution is stable at room temperature for at least 12 months. 